Simian immunodeficiency virus of chimpanzees (SIVcpz) is the precursor of human immunodeficiency virus type 1 (HIV-1), the cause of the AIDS pandemic (1-3). For the past decade, our group has studied SIVcpz infection of wild-living chimpanzees, combining non-invasive virus detection with studies of chimpanzee behavior, life history, fertility and mortality (1-60). These investigations have provided unprecedented insight into the biology and pathogenicity of SIVcpz (4-6), its prevalence and geographic distribution (7-9), its zoonotic potential (8, 10-12), and its ability to counteract potent human restriction factos (12-19). We also examined the ecology, behavior, genetics and population history of wild chimpanzees (20-42), and discovered novel viruses (43-45), parasites (46-50) and microbiota (51-56) in their fecal samples, including the precursors of other major human pathogens (46, 47, 57). Most of this work was conducted in Gombe National Park, the only field site in the world where SIVcpz infection can be studied in habituated chimpanzees at close range. In this application, we propose to capitalize on these findings, many of which are only now coming to fruition, and to continue to conduct non-invasive investigations of SIVcpz infected wild-living apes to aid their survival as well as to enhance human health. Our working hypothesis is that studies of the precursor of the human AIDS virus in its natural chimpanzee host will continue to reveal critical new insight into HIV/SIV pathogenesis and lead to new interventions that will benefit both humans and chimpanzees. Taking advantage of the unique ecology, existing knowledge base and research infrastructure in Gombe, we will continue to study the pathobiology of SIVcpz and its impact on the three resident chimpanzee communities, assessing for the first time the necessity and feasibility of interventions aimed at reducing SIVcpz transmission (Aim #1). We will also expand our field studies to the Greater Mahale Ecosystem (GME), which is home to ~2,500 highly endangered savanna chimpanzees, to determine to what extent SIVcpz has penetrated this much larger and more diverse population (Aim #1). To identify new barriers of zoonotic transmission, we will determine why adaptation of the Gag protein was required each time ape viruses crossed the species barrier to humans, and elucidate how one particular amino acid residue at position 30 of the viral matrix protein (Gag-30) increases SIVcpz resistance to type 1 interferons (IFNs) in human CD4+ T cells (Aim #2). Finally, we will explore whether monoclonal antibodies and immunoadhesins that potently neutralize diverse strains of HIV-1 can be used for vectored immunoprophylaxis and/or therapy to combat SIVcpz infection (Aim #3). Execution of these aims will not only uniquely complement ongoing pathogenesis, prevention and cure research in HIV-1, but will lay the groundwork for feasibility studies aimed at translating interventions developed for HIV-1 infected humans to benefit SIVcpz infected chimpanzees.